Design and Methods of Case Control Studies

1. Neuroepidemiology Teaching Course: Non-Experimental Neuroepidemiology Chisinau Moldavia September 26 2012 Design and Methods of Case Control Studies Giancarlo Logroscino MD PhD Department of Neurology and Psychiatry University of Bari. Italy

2. When Did Lou Gehrig’s Personal Illness Begin?Kasarskis et al, Neurology, 1989; 39:1243-1245 0.400 0.350 Batting average 0.300 0.250 Yankee teammates (n=9) (x±SD) 0.200 Gehrig 0.150 0.100 -10 -9 -8 -7 -6 -5 -4 -3 -2 R Years

3. ALS and Soccer

4. The Question: Is trauma a risk factor for ALS? • Rare disease • Neurodegenerative chronic disease • Induction period is unknown probably some years before disease onset

8. Classification of Studies Descriptive Studies Populations Frequency Distribution by time Place Person • Analytic Studies • Counting exposure and outcomes in individuals • Test causal hypotheses • Uncontrolled assignment • Experimental Studies • Counting exposure and outcomes in individuals • Test causal hypotheses • Controlled assignment RandomizedClinical Trial Population Survey Case-Control Cohort

9. Natural History of Disease and Case-control Studies Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford ALS ALS C C C C Disease is known Exposure unknown C ALS C C ALS ALS C C C Past Now

10. Case Control Design: Advantages • Useful for rare conditions • Short duration • Relatively inexpensive • Relatively small • Study more than one exposure • Measure of effect is the odds ratio (OR)

11. What are the Odds? • The odds in favor of an event or a proposition are the ratio of the probability that an event will happen to the probability that it will not happen. • For example, the odds that a randomly chosen day of the week is a Sunday are one to six, which is sometimes written 1:6, or 1/6.[1] • 'Odds' are an expression of relative probabilities. A bookmaker may use 'odds' of 'one-sixth', but a more common use is "odds against", of the form 6 to 1,

13. Case Control: Problems • Bias from Sampling • Does not establish sequence of events (Temporality) • Potential Bias in Measuring Predictors • Potential Survivors Bias • Only one outcome ( disease) • Does not estimate incidence and risk

14. Population Concept of a Case-control Study Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford C ALS • Find Cases (ALS) • Define Controls (C) • Base population ALS C C ALS C ALS C C ALS Exposure? Exposure? time future now past

15. Selection of Controls • Given a set of cases is to select controls who aproximate the exposure prevalence of the population who generated the cases • Key Comparison is that of controls with the source population they are intended to approximate • Biased study originate because the controls do not reflect the exposure prevalence in the reference population

16. Goal of the Unexposed in Cohort Studies • Tp provide an estimate of the disease rate that the exposed group would have had, had they not be exposed • Counterfactual comparison • trial

17. Who are the right controls? Conceptual questions • Comparable to the cases ? • Representative of all non diseased people • Practical Questions • Resources • Time • Sample size

18. Source population Cases Exposed Sample Unexposed • Controls: • Sample of the denominator • Representative with regard to • exposure Controls

19. Study Sample Target Sample Target Population Study Design Study Implementation Measurement

20. Interpreting the results of a case-control study of coffee drinking and pancreatic cancer Difference in exposure Percent Drinking Coffee Cases Controls

21. Population Concept of a Case-control Study Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford C ALS • Find Cases (ALS) • Define Controls (C) • Base population ALS C C ALS C ALS C C ALS Exposure? Exposure? time future now past

22. Registers and RegistriesLast JM A Dictionary of Epidemiology Oxford 1987: 112 • Ongoing registration of all cases of a particular disease or other health relevant condition in a geographically defined population. With this information incidence rates can be calculated. • If the case are regularly followed up, information on remission, exacerbation, prevalence and survival can also be obtained • Register is the document and registry is the ongoing registration system

23. The Amyotrophic Lateral Sclerosis Incidence in Puglia, Southern Italy SLAP Registry

24. ALS Center

25. Strengths : Multiple sources of case-ascertainment Defined geographic area Prospective collection of data Same diagnostic criteria: EEC Limitations only 60-80 cases per registry/year EURALS Population-Based Registries in Europe • Catchment pop.: 24 million 2

26. Sources of Cases • Departments of Neurology • Neurophysiologic Units • Area Neurologists • ALS Association • National Centers for ALS quaternary referral

27. Advantages of Case-Controls Using Registries • Clear definition of population-time experience that produces the ALS cases • Geographic boundaries • Calendar periods • Full roster of the cases

28. Study Sample Target Sample Target Population Who are the cases in my study? Study Design Study Implementation Measurement

29. Who would have became a ALS case in our study ? • Whether symptoms came to attention • Whether subjects in that population seek diagnosis for those symptoms • Whether they have access to medical care • Who they chose as their health care provider • Willingness to participate to the study

30. EURALS: The Incident Cases Scotland Puglia 130 231 194 154 54 265 Ireland Lombardia Lancashire Piemonte N=1028

31. Population Concept of a Case-control Study Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford C ALS • Find Cases (ALS) • Define Controls (C) • Base population ALS C C ALS C ALS C C ALS Exposure? Exposure? time future now past

32. Study Sample Target Sample Target Population Who are the controls in my study? Study Design Study Implementation Measurement

33. EURALS: The Reference Population Scotland Puglia 5.1 4.0 4.9 3.7 1.7 4.4 4.4 Ireland Lombardia Lancashire Piemonte N=23.869.485

34. Possible Controls • Neighborhood controls • Random digit dialing • Best friend controls / spouses • Hospitalized controls

35. European CC ALS Study: Issues to be considered in Controls Selection • Large area with NHS but not homogenous levels of access to care and to ALS care • Very different habits for physical activity and access to professional sports especially in the age groups of ALS cases • Physical activity and type of physical activity is a social behavior strongly conditioned by SES and cultural characteristics (broad range across bas population)

36. Possible Definition of Control • Those who had been resident in the same area at the time of case diagnosis for one year. • Source of sampling: the roster of the GP who referred the case • Matched for age and gender

37. Physician refusal of access to the patient • Perceived vulnerability of the patient • Perceived hostility of the patient • GP attitude toward patient autonomy

38. Population Concept of a Case-control Study Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford C ALS • Find Cases (ALS) • Define Controls (C) • Base population ALS C C ALS C ALS C C ALS Exposure? Exposure? time future now past

39. RISK OF TRAUMA IN ALS PATIENTS AND CONTROLS BY NUMBER OF EVENTS

40. RISK OF ALS BY SEVERITY OF TRAUMA

41. Beghi et al, unpublished ALS & COFFEE

42. Natural History of Disease and Case-control Studies Bhopal R. Concept of Epidemiology. An Integrated Introduction to the Ideas, Theories, Principles and Methods of Epidemiology. 2002 Oxford University Press, Oxford AD AD C C C C Disease is known Exposure unknown C AD C C AD AD C C C Past Now

43. Does Smoking • Cause Dementia?

44. Selected Case-Control Studies of Alzheimer’s Disease and Smoking (as Rewied by Lee[1999])Kukull W A. Biol Psychiary 2001;49:194-199

45. Smoking and AD: Conflicting Results from Cohort Studies ? Brayne Broe Wang Tyas Doll&Peto Merchant Launer Juan Ott 2,0 2.5 0.67 1.0 1.5 0.40 0.50 Protective effect Harmful effect Null

46. Problems with case-control studies • Retrospective assessment of exposure to smoking • Recall bias • Prevalent cases of dementia • Incidence/prevalence bias • Biased selection of controls • Smokers overrepresented in hospital controls • These problems may result in downwardly biased estimates

47. Selection of Cases In CC Design

48. Potential Contribution of Study DesignBhopal R, Concepts of Epidemiology, Oxford 2002 Criteria Cross-sectional Case-control Cohort Trial Temporality Sometimes Sometimes Often Usually Strength or Dose-response Always Always Sometimes Often Experimental confirmation Sometimes (repeated studies) Sometimes (natural changes) Seldom Always Yes (risk or preventive factor(s)) Yes (disease) Yes (risk factor(s)) Specificity Sometimes Biological Plausibility Not Directly Not directly Not directly Not directly Consistency Yes Yes Yes Yes